The Rad9-Hus1-Rad1 (9-1-1) clamp activates checkpoint signaling via TopBP1

Sinny Delacroix, Jill M. Wagner, Masahiko Kobayashi, Ken Ichi Yamamoto, Larry M. Karnitz

Research output: Contribution to journalArticle

309 Scopus citations

Abstract

DNA replication stress triggers the activation of Checkpoint Kinase 1 (Chk1) in a pathway that requires the independent chromatin loading of the ATRIP-ATR (ATR-interacting protein/ATM [ataxia-telangiectasia mutated]-Rad3-related kinase) complex and the Rad9-Hus1-Rad1 (9-1-1) clamp. We show that Rad9's role in Chk1 activation is to bind TopBP1, which stimulates ATR-mediated Chk1 phosphorylation via TopBP1's activation domain (AD), a domain that binds and activates ATR. Notably, fusion of the AD to proliferating cell nuclear antigen (PCNA) or histone H2B bypasses the requirement for the 9-1-1 clamp, indicating that the 9-1-1 clamp's primary role in activating Chk1 is to localize the AD to a stalled replication fork.

Original languageEnglish (US)
Pages (from-to)1472-1477
Number of pages6
JournalGenes and Development
Volume21
Issue number12
DOIs
StatePublished - Jun 15 2007

Keywords

  • ATR
  • Checkpoint
  • Chk1
  • Rad9
  • Replication
  • TopBP1

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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